Found: A Home for Itch in Peripheral Neurons

Pain can block the sensation of itch, for example, and pain-quelling opioids can unleash itchiness. Neurological diseases including shingles, peripheral neuropathy, and stroke can cause neuropathic pain or neuropathic itch, or both. And at the cellular level, the two sensations appear to share common origins, since both initiate in C-fiber nociceptors.

Now, researchers have taken a step toward disentangling itch from pain, with the identification, in mice, of a set of nociceptors that specifically signal itch.

The work, led by Xinzhong Dong at Johns Hopkins University School of Medicine, Baltimore, Maryland, US, and Robert LaMotte at Yale University School of Medicine, New Haven, Connecticut, US, appeared online December 23 in Nature Neuroscience.

Itch is a major clinical problem with many causes, from drug side effects to neurological disease. The discovery of itch-specific nociceptors will enhance understanding of the signaling systems involved, and could facilitate the search for anti-itch treatments, said Allan Basbaum, a pain neuroscientist at the University of California, San Francisco, US, who was not involved in the study.

The researchers devised an elegant strategy to selectively activate a particular subset of C-fiber nociceptors, Basbaum said. “And they were able to demonstrate that this population produces itch, not pain.”

A strength of the paper is “the integration of multiple methods including morphological, molecular, electrophysiologic, and behavioral analyses to characterize these neurons both in vitro and in vivo,” added Anne Louise Oaklander, a neurologist and investigator at Harvard Medical School, Boston, Massachusetts, US, who was not involved in the study. “An interesting finding is that these neurons only innervate the epidermis, since itch sensation is more restricted than pain on the body. Itch is limited to the skin and superficial mucosa, but not to the internal organs.”

Nociceptors in name only?

In the hunt for itch-specific cells, Dong and LaMotte focused on a small population of dorsal root ganglion neurons that express the Mas-related G protein-coupled receptor MrgprA3. Dong’s lab had found previously that MrgprA3 on neurons serves as a receptor for the anti-malarial drug chloroquine, and is required to develop the severe itch often induced by the drug. MrgprA3-expressing cells also fire in response to histamine and other itch-inducing substances (pruritogens) (Liu et al., 2009).

But like pruritogen-responsive C-fibers in people (Schmelz et al., 2003), the researchers found in their new study that the MrgprA3-expressing cells were also activated by painful stimuli—high heat, strong force, or capsaicin. That raised the question, Were the neurons capable of relaying both itch and pain signals, depending on the stimulus, or might they be hardwired to produce only the sensation of itch?

To answer that question, first author Liang Han and coworkers used a targeted toxin strategy to chemically ablate only MrgprA3-positive neurons in adult mice. That dramatically reduced the animals’ scratching in response to injection of pruritogens and also in models of chronic itch due to dry skin or allergic reaction. However, the animals behaved normally in a battery of tests for acute and inflammatory pain, suggesting that MrgprA3-postive neurons do not signal pain.

To solidify the case, the researchers did the opposite experiment: Instead of killing the cells, they activated them. Using mice deficient for the transient receptor potential channel TRPV1 (the “capsaicin receptor”), the team reintroduced TRPV1 only in MrgprA3-expressing cells, so that administering capsaicin would turn on only those neurons. Normally, capsaicin causes pain, but when the engineered mice were exposed to capsaicin, they acted as mice do when something itches: They scratched.

“We turned a painful stimulus into an itchy stimulus,” Dong said.

The results suggest that MrgprA3-expressing neurons are dedicated to evoking itch. “No matter how you activate this type of neuron, the animal will perceive it as itch, not as pain,” Dong said.

Researchers have long debated whether itch-specific neurons exist (“specificity theory”), or whether a common set of primary sensory neurons convey both itchy and painful messages, leaving the central nervous system to sort out the difference (“patterning theory”; see related PRF Discussion by Basbaum). The new study is “one of the most impressive demonstrations” of specificity, Basbaum said.

Still, researchers have ample reason to scratch their heads about how primary sensory neurons signal itch. To start, “there’s not just one pruritogen. There are many, many pruritogens,” Basbaum said. That means MrgprA3-positive cells do not solve the puzzle of itch, he said—they are just the beginning of the story.

Another major issue is chronic itch, and Dong said his group is now investigating how MrgprA3-expressing neurons change in models of chronic itch, and what role the cells may play in those settings.

Comments

Han et al. have provided a thorough and novel investigation that demonstrates the existence of itch-specific nerve fibers in mice skin. These MrgprA3 nerve fibers explain the missing link of why itch emanates from C nerve fibers in upper layers of the skin while similar fibers transmit pain from deeper layers of skin. However the applicability of this model in chronic itch in humans requires further studies. My clinical understanding in recent years is that there is an overlap with pain in chronic itch, as sufferers complain also of features of burning pain sensations albeit less than in chronic pain. Therefore a simple model of chronic itch transmission via several so called specific receptors is an over-simplification of the complexity of chronic itch. The fact that MrgprA3 has a unique role for cholorquine-induced itch, which has limited effect on itch in humans except in African ethnicity, suggest that this receptor may have a different role in chronic itch in humans.